Compounds of estrogen-related receptor modulators and the uses thereof

ABSTRACT

The compounds according to formula (VIII), their pharmaceutically acceptable acid or base addition salts, and the uses thereof. These compounds and their pharmaceutically acceptable acid or base addition salts can be used for preparing medicaments for modulating estrogen related receptors (ERR), and treating metabolic diseases, such as high blood fat, fatty liver, hyperglycemia, diabetes, obesity. The substituents of the formula are defined in the description.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/054,664, filed on May 20, 2011, issuing, which is the U.S. NationalPhase of International application No. PCT/CN2009/000243, filed Mar. 6,2009, which claims priority to Chinese Patent Application No. CN200810029586.9, filed Jul. 18, 2008. The entire contents of all of theaforementioned patent applications are hereby expressly incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to small molecules which function as modulatorsof estrogen-related receptors.

BACKGROUND OF THE INVENTION

In recent years, the increasing incidences of metabolic diseasesincluding obesity, diabetes, dyslipidemia, hypertension, andatherosclerosis, have led to higher risks of heart 10 diseases, aleading cause of mortality worldwide. The healthcare cost associatedwith treatment is putting major burdens on the healthcare systems ofdeveloped as well as developing countries. Therefore, identifying noveltargets and pharmacologic agents to treat and/or prevent these disordersare of high priorities.

Both type 1 (insulin-dependent diabetes mellitus, IDDM) and type 2)noninsulin-dependent diabetes mellitus, NIDDM), diabetes arecharacterized by elevated levels of plasma glucose (hyperglycemia) inthe fasting state or after administration of glucose during an oralglucose tolerance test. Insulin is the hormone that regulates glucoseutilization by stimulating glucose and lipid metabolism so the maininsulin-sensitive tissues including muscle, liver and adipose tissues.Inappropriate regulation of energy metabolism in these tissues accountsfor most of the alterations in glucose homeostasis seen in patients withtype 2 diabetes. In addition, patients having type 2 diabetes often havehyperinsulinemia (elevated plasma insulin levels). Insulin resistance,which means a resistance to the effect of insulin, plays an early rolein the pathogenesis of type 2 diabetes.

Skeletal muscle and liver are both key insulin-responsive organsresponsible for maintaining normal glucose homeostasis. Mitochondrialdysfunction has been closely associated with skeletal muscle insulinresistance in several studies. In skeletal muscle of human type IIdiabetics, the expression levels of mitochondrial oxidativephosphorylation (OXPHOS) genes are reduced. The OXPHOS genes that aredysregulated in type II diabetic patients are under the transcriptionalcontrol of peroxisome proliferator-activated receptor

coactivator-

(PGC-1α). The reduction of PGC-1α level will in theory induce thereduction of the OXPHOS genes and reduce the oxidation of fatty acids,and thus result in the reducing of lipid deposition in the skeletalmuscle, and finally induce insulin resistance and type II diabetes.Actually, the imbalance of PGC-1α is a common phenomenon ofpre-diabetics. This further proves that the reduction of PGC-1α level isan important factor inducing the diabetes.

Estrogen-related receptors (ERRs) are a kind of nuclear hormone receptorclosely related to the estrogen receptor α. During the binding of theERRs and their co-activator, no exogenous ligands and endogenous ligandsparticipate, which is considered to construct constitutively activeorphan nuclear hormone receptors. Studies show that ERRs include 3 kindsof different subtypes, i.e. ERRα, ERRβ and ERRγ (related documents:Giguere, V., Nature, 1988, 331, 91˜94; Hong, H J. Biol. Chem. 1999, 274,22618-22626; Heard, D. J. Mol. Endocrinol. 2000, 14, 382-392; Giguere,V. T. Trends. Endcrinol. Metab. 2002, 13(5), 220-226; etc.). ERRβ mainlyrelates to the upgrowth of organisms, and its expression is strictlycontrolled after birth, and there is a small amount of expression to theliver, stomach, skeletal muscle, heart and kidney. The expression ofERRγ mainly lies in the spinal cord and the centra nervous system. ERRαmainly exists in metabolically active tissues or organs such as skeletalmuscle, heart, kidney and adipose tissue (related documents: Giguere,V., Nature, 1988, 331, 91˜94; Sladek, R. Mol. Cell. Biol. 1997, 17,5400˜5409; etc.), and the interaction of ERRα and PGC-1 (peroxisomeproliferator activated receptor γ (PPAR-γ) coactivator 1) controls thetranscription of mitochondrial oxidative phosphorylation (OXPHOS) genesand regulates the material and energy metabolism of glucose and adipose(related documents: Schreiber, S. N. Proc. Natl. Acad. Sci. U.S.A. 2004,101, 6472˜6477; Schreiber, S. N. J. Biol. Chem. 2003, 278, 9013˜9018;Huss, J. M. J. Biol. Chem. 2002, 277, 40265-40274; Ichida, M.; Nemoto,S. J. Biol. Chem. 2002, 277, 50991-50995; etc.).

The OXPHOS is the most crucial step during the ATP energy generating bymaterial metabolism of the glucose, adipose, etc. PGC-1 is an importantregulator of the OXPHOS and plays an important regulation role duringthe heat generation in the tissues such as skeletal muscle and brownadipose, and respiration and mitochondrial biogenesis in the musclecell, and the transition of skeletal muscle fiber. Furthermore, PGC-1also controls the expression of genes for encoding many kinds ofgluconeogenic enzymes (related documents: Mootha, V. K. Nat. Genet.2003, 34, 267-273; Patti, M. E. Proc. Natl. Acad. Sci. USA 2003, 100,8466-8471; Puigserver, P. Endocr. Rev. 2003, 24, 78-90. Studies showthat the reduction of PGC-1 may affect the metabolism of energymaterials such as glucose and adipose, and induce excess blood glucoseand lipid deposition in the skeletal muscle, and finally induce insulinresistance and type II diabetes.

ERRα is the direct downstream target gene of PGC-1α. The directinteraction of ERRα and PGC-1α controls the transcription of genes suchas OXPHOS and fatty acid oxidase so as to regulate the process of OXPHOS(Mootha, V. K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6570-6575).Studies show that under the stimulation of environment signals such asfasting, physical training, and cold, PGC-1α may facilitate theexpression of ERRα, and further facilitate the transcription of ERRα byway of binding with ERRα to induce ERRα to bind with the specificbinding site of gene promoter of itself. The interaction between thePGC-1α and ERRα, can further promote the binding of ERRα with the otherdownstream gene promoters of PGC-1α, and facilitate the transcription ofthese downstream functional genes (such as phosphoenolpyruvatecarboxykinase (PEPCK), medium chain acyl dehydrogenase (MCAD), andpyruvate dehydrogenase kinase 4 (PDK4)), and thus control the OXPHOS andthe fatty acid oxidation effectively and promote the metabolism of fattyacid and glucose (FIG. 1A) (related documents: Schreiber, S. N. et al.Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6472˜6477, Willy, P. J.; et al,Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8912˜8917, etc.).

Therefore, with small molecular compounds especially small molecularpromoter ERRα regulates the function of ERRα and PGC-1α, the function ofOXPHOS genes is effectively improved, the oxidization of fatty acid isfacilitated or the utilization of glucose is reduced, and it can be usedas an affective way to cure diabetes and the related obesity,hyperglycemia, low blood glucose tolerance, insulin resistance,hyperlipidemia, lipid disorders, high blood cholesterol, hightriglyceride, hypercholesteremia, low high-density lipoproteincholesterol levels, high low-density lipoprotein level, atherosclerosis,and its secondary disease, narrow blood vessels, abdominal obesity,metabolic syndrome and fatty liver. Furthermore, since the smallmolecular promoter ERRα can improve the expression of PGC-1α gene andincrease the sensitivity of insulin. Therefore, they can also be usedwith other insulin sensitizer or insulin secretagogues to improve theclinical effect.

In addition, reduction of estrogen levels in post-menopausal results inan increase of bone loss leading to osteoporosis. Over-expression ofERRα in osteoblasts increases bone nodule formation, while reducing theexpression by anti-sense results in a decrease of bone nodule formation.Therefore, compounds that enhance the activity of estrogen relatedreceptors (ERRα, β, and γ, etc.) activity may have an anabolic effectfor the regeneration of bone density. Conversely, with respect to bonediseases that are a result of abnormal bone growth, compounds that willinteract with estrogen related receptors (ERR α, β, and γ) and decreaseits biological activity may provide a benefit for the treatment of thesediseases by retarding bone growth.

Although estrogen related receptors alpha, beta and gamma (ERRα, ERRβand ERRγ) are considered to be orphan nuclear hormone receptors thatdisplay constitutively active transcriptional activities, syntheticphenolic acyl hydrazones have recently been demonstrated to be selectiveERRβ and ERRγ agonists through binding to the C-terminally locatedligand binding domain (LBD) and activating its function. However, nodefinitive ERRα agonist has been identified so far that would improveinsulin resistance through enhancing the function of PGC1.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide compounds as theestrogen-related receptor modulators.

In an embodiment, this invention provides compounds having formula VIIIand their pharmaceutical acceptable salts and stereo isomers:

wherein,

m is 0, 1 or 2;

n is 0, 1 or 2;

in the following, a is 0 or 1, b is 0 or 1;

R₁ and R₇ are independently selected from:

1) H;

2) Halo;

3) OH;

4) (C═O)_(a)O_(b)C₁˜C₄ alkyl;

5) (C═O)_(a)O_(b)C₃˜C₆ cycloalkyl;

R₂ is selected from:

1) H;

2) C₁˜C₃ alkyl;

3) C₃˜C₆ cycloalkyl;

the alkyl mentioned above can be substituted by 0, 1 or more substitutedgroups independently selected from R₄

R₄ is selected from:

1) H;

2) C₃˜C₆ heterocyclyl.

The invention also provides a pharmaceutical, composition containing anyone of the compounds mentioned above or their pharmaceuticallyacceptable salts or pro-drugs thereof. The pharmaceutical compositioncan be used as a new class of therapeutics for the treatment ofmetabolic diseases.

The present invention relates to the use of the compounds mentionedabove and their pharmaceutical acceptable salts which function asmodulators of estrogen-related receptors as a new class of therapeuticsfor the treatment of metabolic diseases.

Preferably, the metabolic diseases includes: (1) Type II diabetes; (2)hyperglycemia; (3) reduced glucose tolerance; (4) insulin resistance;(5) obesity; (6) hyperlipidemia; (7) hypertriglyceridemia; (8)hypercholesteroimia; (9) low levels of HDL; (10) high levels of LDL;(11) atherosclerosis; (12) vascular restenosis; (13) fatty liver.

The present invention provides compounds represented by Formula VIII,which are agonists of estrogen-related receptors (ERRα, β, and γ, etc).The invention also relate to the use of compounds of the invention totreat a subject suffering from or diagnosed with metabolic diseases likeType II diabetes and associated hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity and fatty liver.

The present invention contemplates that compounds which agonize thefunctions of ERRα and its interacting partner PGC-1α will alleviate theextent of insulin resistance, improve glucose homeostasis in diabeticpatients and restore insulin sensitivity. The present inventioncontemplates these compounds may reduce blood glucose levels anddiabetic serum marker hemoglobin A1c glycosylation level. Furthermore,the present invention contemplates that ERRα agonists may enhance thetherapeutic effects of current and developing insulin sensitizers andinsulin secertagogues when used in combination.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing the effect of DK compounds on the activityof ERRα;

FIG. 2 is a diagram showing the effect of DK45 on the reporter geneexpression of the promoter PGC1α driven by ERRα;

FIG. 3 is a diagram showing the effect of DK45 on the oral glucosetolerance;

FIG. 4 is a diagram showing the effect of DK45 on the blood glucoselevel (without fasting);

FIG. 5 is a diagram showing the effect of DK45 on the insulin tolerance;

FIG. 6 is a diagram showing the effect of DK45 on the blood insulinlevel;

FIG. 7 is a diagram showing the effect of DK45 on the blood fatty acidlevel;

FIG. 8 is a diagram showing the effect of DK45 on the total bloodcholesterol level;

FIG. 9 is a diagram showing the effect of DK45 on the bloodtriglyceride.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The compounds related to the invention could have chiral center, chiralaxis or chiral surface. They may have racemate. All the stero isomers,racemate mixtures and other isomers are included in the invention. Thecompounds related to the invention may have tautomers. Although there isonly one taumoter is descripted, the invention included all the possibletaumoters.

In this invention, the term “alkyl” and “sub-alkyl” means aranched-chain or straight chain alkyl group with certain number ofcarbon atoms. For example, the “C₁-C₅” in “C₁-C₈ alkyl” is defined tostraight-chain or branched-chain alkyl group with 1,2,3,4,5,6,7 or 8carbon atoms. “C₁-C₈ alkyl” includes methyl, ethyl, n-propyl, isopropyl,n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl-, octyl, etc. Theterm “cycloalkyl” refers to a specific single saturated ring alkyl withcertain number of carbon atoms. For examples, “cycloalkyl” includescyclopropyl-, methyl-cyclopropyl-, 2,2-dimethyl-cyclobutyl,2-ethyl-cyclapentadienyl-, cyclohexyl etc.

“Alkoxy” means a sunstituent connecting certain number of carbon atomsof the cyclic alkyl or noncyclic alkyl group through oxygen atom.

“Heterocycle” is an aromatic or nonaromatic ring containing 5˜10 atoms,in which contains 1˜4 hetero atoms such as O, N, S. “Heterocycle”includes the hetero aromatic ring as mentioned above, it also includesdihydro and tetrahydro analogs. “Heterocycles” include but not limit to:benzimidazolyl, benzo furyl, benzopyranyl, benzo pyrazolyl,benzotriazolyl, benzo thienyl, benzoxazolyl, carbazolyl, carbolinyl,miso-phenanthrolinyl, furyl, imidazolyl, dihydro-indolyl, indolyl,indolazinyl, indazolyl, furans, isobenzofuranyl, isoquinolinyl,isothiazolyl, isoxazolyl, Chennai pyridyl, oxadiazolyl, oxazolyl,oxazolinyl, isoxazole morpholinyl, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,quinzaolinyl, quinolyl, tetrahydro pyranyl, tetrazolyl, pyridyltetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,1,4-alkyl-dioxinyl, hexallydroazepinyl, piperazinyl, piperidinyl,pyridine-2-keto, alkyl pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydro-benzimidazolyl, dihydro-benzo furyl, benzo-dihydro-thienyl,dihydro-benzoxazolyl, dihydro-furyl, dihydro-benzimidazolyl,dihydro-indolyl, dihydro-isoxazolyl, dihydro-iso thiazolyl,dihydro-oxadizaolyl, dihydro-oxazolyl, dihydro-pyrazinyl,dihydro-pyrazolyl, dihydro pyridyl, dihydro-pyrimidinyl,dihydro-pyrrolyl, dihydrofolate quinolyl, tetrazolyl dihydro,dihydro-thiadiazolyl, dihydro thiazolyl, dihydro thienyl,dihydro-triazolyl, methylene dioxy benzophenone acyl and their N-oxides,etc. The connection of the heterocyclic ring substituent is realized bycarbon atom or hetero-atom.

In one embodiment, heterocycle is selected as benzimidazolyl,imidazolyl, 2-imidazoline ketone, indole-based, isoquinolinyl,morpholinyl, piperidinyl, piperazinyl, pyridyl, alkyl pyrrole,2-piperidine ketone, 2-pyrimidine ketone, 2-pyrrolidone, quinolyl,tetrahydrofuranyl, tetrahydro isoquinolinyl, thienyl, etc.

As it can be easily understood, halides used in the invention includefluoride, clorine, fluorine, bromine and iodine.

In an embodiment, R₄ may form a mono ring containing 4˜7 atoms or abicyclic ring in which each ring comprises 4˜7 atoms through the N atomwhich connects R5 and R6. The mono ring or bicyclic ring may furthercomprises 1˜2 hetero atoms selected as H, O, S. The mono ring orbicyclic ring can also be substituted by 1 or more sunstituents selectedas R₅. The hetero cyclic rings formed include but not limit to thefollowing heterocycles:

In one embodiment, R₁ is selected as halogen, hydroxy, (C₁-C₆) alkyl, oralkoxy.

In one embodiment, R₂ is selected as H, alkyl, alkyl group substitutedby R₅.

In one embodiment, a is 0, b is 1. In another embodiment, a is 0. b is0.

The invention includes the free forms of compounds with formula VIII andalso the pharmaceutical acceptable salts or stero isomers of formulaVIII. In one embodiment, the special examples in the invention are theprotonated salts of amines. The “free form” means amines which do notform salts with acids. “Pharmaceutical acceptable salts” include all thesalt forms of Formula VIII.

“Pharmaceutical acceptable salts” in the invention mean the salts formedby the basic compounds in the invetion with normal nontoxicic organicacids and inorganic acids. The acids include hot not limit to:hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid,phosphoric acid, nitric acid, acetic acid, propionic acid, succinicacid, glycolic acid, stearic acid, lactic acid, malic acid, tartaricacid, lemon acid, ascorbic acid, bashing acid, maleic acid,hydroxy-maleic acid, phenylacetic acid, glutamic acid, benzoic acid,salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid 1,p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic, oxalicacid, hydroxyethyl sulfonic acid, trifluoroacetic acid, etc.

If the related compounds are acids, “pharmaceutical acceptable salts”mean the salts formed by the acidic compounds in the invention withnormal nontoxicic organic bases or inorganic bases. The salts formed byacidic compounds with inorganic bases include but not limited to:aluminum salt, ammonium salt, calcium salt, copper salt, iron salt,ferrous salt, lithium salt, magnesium salt, manganese salt, manganesesub-salt, potassium, sodium, zinc, etc. ammonium salt, calcium salt,magnesium salt, potassium salt and sodium salt are preferred. Theorganic bases include but not limited to: primary amine, secondaryamine, tertiary amine salts, substituted amines including naturallyoccurring substituted amines, cyclic amines and basic ion exchangeresins such as arginine, betaine, caffeine, choline,N,N′-dibenzyl-ethylenediamine, diethylamine, 1,2 diethyl amino alcohol,dimethyl amino ethanol, amino-ethanol, ethanolamine, ethylenediamine,N-ethyl morpholine, N-ethyl piperidine, glucose amine, glucosamine,histidine, hydroxyproline cobalt amine, isopropyl amine, lysine,methyl-glucosamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purine, pentoxifylline, triethyl amine, trimethylamine, tripropyl amine, tromethamine, etc.

The related compounds can be prepared by using the following method. Ofnote, the synthetic scheme only outlines the examples. The relatedcompounds may have more different substituents and can be made by othermethods.

As shown in the scheme, compound 3 was synthesized according to thefollowing procedure: 2-aminopyridine (1.00 mmol) and the suitable β-ketoester (1.50 mmol) in PPA (2.00 g) was heated at 130□ with frequentstirring. After 4 h, the reaction mixture was cooled in ice bath andneutralized with 5% aqueous sodium hydroxide to allow pH>7. The solidprecipitate was collected by filtration, washed with water, andrecrystallized.

The present invention contemplates that compounds which agonize thefunction of ERRs, especially agonists or partial agonists of ERRα. Somecompounds can functionally stimulate the functions of both ERRα and ERRβand consider ERRα/β dual agonists. Some compounds can functionallystimulate the functions of both ERRα and ERRγ and consider ERRα/γ dualagonists. Some compounds can functionally stimulate the functions ofboth ERRα ERRβ and ERRγ and consider ERRα/β/γ pan-agonists. Theinvention also relate to the use of compounds of the invention to treata subject suffering from or diagnosed with a disease, disorder, ormedical condition mediated by estrogen-related receptors.

The present invention contemplates that compounds which agonize thefunctions of ERRα and its interacting partner PGC-1α will alleviate theextent of insulin resistance, improve glucose homeostasis in diabeticpatients and restore insulin sensitivity. The present inventioncontemplates these compounds may reduce blood glucose levels anddiabetic serum marker hemoglobin A1c glycosylation level. The presentinvention provides kits comprising compounds or their pharmaceuticalacceptable salts for administering to an animal or patients withsymptoms of type II diabetes.

In one embodiment, this present invention provides a method of using ERRmodulators for treatment of type II diabetes.

In another embodiment, this present invention provides a method of usingcompounds with Formula VIII or their pharmaceutical acceptable salts fortreatment of patients or animals with related diseases.

In another embodiment, this present invention provides a method of usingcompounds mentioned or their pharmaceutical acceptable salts fortreatments of diseases related to ERR including but not limited to: (1)Type II diabetes; (2) hyperglycemia; (3) reduced glucose tolerance; (4)insulin resistance; (5) obesity; (6) hyperlipidemia; (7)hypertriglyceridemia; (8) hypercholesterolemia; (9) low levels of HDL;(10 ) high levels of LDL; (11) atherosclerosis; (12) vascularrestenosis; (13) fatty liver.

In another embodiment, this present invention relates to compounds ortheir pharmaceutical acceptable salts for treatments of osteoporosis orrelated diseases.

In another embodiment, this present invention provides a method of usingcompounds mentioned or their pharmaceutical acceptable salts fortreatments of hyperglycemia, atherosclerosis, low HDL levels, high LDLlevels, hyperlipidemia, hypertriglyceridemia, etc.

The compound may be used alone or advantageously may be administeredwith a cholesterol biosynthesis inhibitor particularly an HMG-CoAreductase inhibitor such as lovastatin, simvastatin, rosuvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, orZD-4522. The compound may also be used advantageously in combinationwith other lipid lowering drugs such as cholesterol absorptioninhibitors (for example stanol esters, sterol glycosides such astiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such asavasimibe), CETP inhibitors, niacin, bile acid sequestrants, microsomaltriglyceride transport inhibitors, and bile acid reuptake inhibitors.These combination treatments may also be effective for the treatment orcontrol of one or more related conditions selected from the groupconsisting of hypercholesterolemia, atherosclerosis, hyperlipidemia,hypertriglyceridemia, high LDL levels, low HDL levels, etc.

Another aspect of the invention provides a method of treatinginflammatory conditions, including inflammatory bowel disease, Crohn'sdisease, and ulcerative colitis by administering an effective amount ofa compound of this invention to a patient in need of treatment.Additional inflammatory diseases that may be treated with the instantinvention include gout, rheumatoid arthritis, osteoarthritis, multiplesclerosis, asthma, ARDS, psoriasis, vasculitis, ischemia/reperfusioninjury, frostbite, and related diseases.

The compounds as defined herein may be used to treat diseases accordingto the following methods, as well as other diseases not listed below:

(1) A method for treating non-insulin dependent diabetes mellitus (type2 diabetes) in a human or other mammalian patient in need of suchtreatment which comprises administering to the patient a therapeuticallyaffective amount of a compound of Formula VIII;

(2) A method for treating or controlling hyperglycemia in a human orother mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula VIII;

(3) A method for treating or controlling obesity in a human or othermammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula VIII;

(4) A method for treating or controlling hypercholesterolemia in a humanor other mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula VIII;

(5) A method for treating or controlling hypertriglyceridemia in a humanor other mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula VIII;

(6) A method for treating or controlling one or more lipid disorders,including sow HDL cholesterol, high LDL cholesterol, hyperlipidemia,hypercholesterolemia, and hypertriglyceridemia in a human or othermammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula VIII;

(7) A method for reducing the risks of adverse sequelae associated withmetabolic syndrome in a human or other mammalian patient in need of suchtreatment which comprises administering to the patient a therapeuticallyeffective amount of a compound of Formula VIII; and

(8) A method for treating atherosclerosis, for reducing the risk ofdeveloping atherosclerosis, for delaying the onset of atherosclerosis,and/or reducing the risk of sequelae of atherosclerosis in a human orother mammalian patient in need of such treatment or at risk ofdeveloping atherosclerosis or sequelae of atherosclerosis, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula VIII. Sequelae of atherosclerosisinclude for example angina, claudication, heart attack, stroke, etc.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage forms,include tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula VIII are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or controlling diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of FormulaVIII are indicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.1 milligram to about 500 milligram per kilogram of animalbody weight, preferably given as a single daily dose or in divided dosestwo to four times a day, or in sustained release form. For most largemammals, the total daily dosage is from about 0.1 milligrams to about1500 milligrams, preferably from about 0.5 milligram to about 100milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 1 milligram to about 500 milligrams. For aparticularly potent compound, the dosage for an adult human may be aslow as 0.1 mg. The dosage regimen may be adjusted within this range oreven outside of this range to provide the optimal therapeutic response.

Oral administration will usually be carried out using tablets. Examplesof doses in tablets are 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5mg, 10 mg, 25 mg, 50 mg, 100 mg, and 250 mg. Other oral forms can alsohave the same dosages (e.g. capsules).

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula VIII and apharmaceutical acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula VIII or apharmaceutically acceptable salt as an active ingredient, as well as apharmaceutically acceptable carrier and optionally other therapeuticingredients. The term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic bases or acids and organic bases or acids. Apharmaceutical composition may also comprise a pro-drug, or apharmaceutically acceptable salt thereof, if a prodrug is administered.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula VIII can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, miorocrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragaeanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate, anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula VIII may also be administered parenterally.Solutions or suspensions of these active compounds can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions, or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions, in all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Metabolites-Prodrugs

Therapeutically active metabolites, where the metabolites themselvesfall within the scope of the claimed invention, are also compounds ofthe current invention. Prodrugs, which are compounds that are convertedto the claimed compounds as they are being administered to a patient orafter they have been administered to a patient, are also compounds ofthis invention.

Combination Therapy

Compounds of Formula VIII may be used in combination with other drugsthat may also be useful in the treatment or amelioration of the diseasesor conditions for which compounds of Formula VIII are useful. Such otherdrugs may be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of FormulaVIII. When a compound of Formula VIII is used contemporaneously with oneor more other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula VIII ispreferred. However, the combination therapy also includes therapies inwhich the compound of Formula VIII and one or more other drugs areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more other active ingredients,the compound of the present invention and the other active ingredientsmay be used in lower doses than when each is used singly. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of Formula VIII.

Examples of other active ingredients that may be administered incombination with a compound of Formula VIII, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

1) PPAR gamma agonists and partial agonists, including both glitazonesand non-glitazones (e.g. troglitazone, pioglitazone, englitazone,MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512,and LY-818);

2) biguanides such as metformin and phenformin;

3) protein tyrosine phosphatase-IB (PTP-1B) inhibitors;

4) dipeptidyl peptidase IV (DP-IV) inhibitors;

5) insulin or insulin mimetics;

6) sulfonylureas such as tolbutamide and glipizide, or relatedmaterials;

7) α-glucosidase inhibitors (such as acarbose);

8) agents which improve a patient's lipid profile, such as (i) HMG-CoAreductase inhibitors (lovastatin, simvastatin, rosuvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522and other statins), (ii) bile acid sequestrants (cholestyramine,colestipol, and dialklylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil,clofibrate, fenofibrate and bezafibrate), (v) cholesterol absorptioninhibitors, such as for example ezetinibe, (vi) acyl CoA:cholesterolacyltransferase (ACAT) inhibitors, such as avasimibe, (vii) CETPinhibitors, and (viii) phenolic antioxidants, such as probucol.

9) PPARα/γ dual agonists, such as KRP-297, muraglitazar, tesaglitazar,farglitazar, and JT-501;

10) PPARδ agonists such as those disclosed in WO097/28149;

11) antiobesity compounds such as fenfluramine, dexfenfluramine,phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4ragonists, cannabinoid receptor 1 (CB-1) antagonists/inverse agonists,and beta.3 adrenergic receptor agonists;

12) ileal bile acid transporter inhibitors;

13) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclo-oxygenase 2 selective inhibitors;

14) glucagon receptor antagonists;

15) GLP-1 and its analogs, such as exenitide;

16) GLP-1 receptor agonists.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula VIII with two or more active compoundsselected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors,other PPAR agonists, PTP-1B inhibitors; DP-IV inhibitors, andanti-obesity compounds.

EXAMPLE 1 8-methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

The solution of compound A and 5% mol sodium bromide in thionyl chloridewas refluxed for 24 h, then the residual thionyl chloride was removed invacuo to get compound B, compound B was added dropwisely mathanol at 0°C. the mixture was refluxed for 24 h, then the solvent was removed invacuo. The residue was transferred into ethyl acetate and washed withsaturated aqueous sodium bicarbonate, and brine. The solution was thendried over sodium sulfate, filtered, concentrated and purified by columnchromatography to provide the desired compound C. Compound C in methanolwas added hydrazine (1.5 eqiv), the mixture was refluxed for 4 h andthen cooled to room temperature, filtrated to get compound D.

To an ice-bath solution of compound D in dry tetrahydrofuran was addeddropwise trifluoroacetic acid (1.0 eqiv), followed by t-Butyl nitrite(3.0 eqiv), the mixture was continued to stirred for additional 30 minat the same temperature, then the solvent was removed to get the crudeproduct compound E.

The solution of compound E in dry toluene was refluxed for overnight,then toluene was removed in vacuo. The residue was dissolved intetrahydrofuran, and added aqueous potassium hydroxide (5.0 eqiv, 10N).The reaction mixture was stirred at room temperature for 5 h, and thenpartitioned between dichloromethane and brine. The dichloromethaneextracts were washed with brine, dried with sodium sulfate, andconcentrated in vacuo. Purification by column chromatography to affordedcompound G.

Compound G and H in polyphosphoric acid was heated to 130° C. for 4 h,then cooled to room temperature. The pH was adjusted to >7 with aqueoussodium hydroxide, and it was extracted with dichloromethane, washed withbrine, dried with sodium sulfate, concentrated and purified by columnchromatography to get final compound DK36 (example 1).

¹HNMR (400 MHz, CDCl₃), δ 8.91 (d, J=8.0 Hz, 1), 8.02˜8.05 (m, 2H),7.46˜7.48 (m, 3H) , 6.97 (d, J=2.8 Hz, 1H), 6.76 (dd, J=2.8, 8.0 Hz,1H), 6.71 (s, 1), 3.95 (s, 3H);

MS(ESI), m/z: 2.53 (M+H)⁺.

EXAMPLE 2 8-methoxy-3-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

MS(ESI), m/z: 267 (M+H)⁺.

EXAMPLE 3 8-hydroxy-2-phenyl-4H-pyrido[1,2a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 9.02 (d, J=7.6 Hz, 1H), 8.15˜8.16 (d,J=6.0 Hz, 2H), 7.67˜7.69 (m, 3H), 7.14˜7.17 (m, 2H), 6.80 (s, 1H);

MS(ESI), m/z: 239 (M+H)⁺.

EXAMPLE 4 8-ethoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.95 (d, J=7.6 Hz, 1H), 8.27˜8.29 (m,2H), 7.61˜7.63 (m, 3H), 7.19 (d, J=2.4 Hz, 1H), 7.12 (dd, J=8.0, 2.8 Hz,1H), 6.89 (s, 1h), 4.41 (q, J=6.8 Hz, 2H), 1.51 (t, J=6.8 Hz, 3H);

MS(ESI), m/z: 2.67 (M+H)⁺.

EXAMPLE 5 8-(allyloxy)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.97 (d, J=7.6 Hz, 1H), 8.27˜8.29 (m,2H), 7.61˜7.63 (m, 3H), 7.22 (d, J=2.0 Hz, 1H), 7.17 (dd, J=7.6, 2.0 Hz,1H), 6.90 (s, 1H), 6.15˜6.25 (m, 1H), 5.60 (d, J=17.2 Hz, 1H), 5.46 (d,J=10.4 Hz, 1H), 4.96 (d, J=5.2 Hz, 2H);

MS(ESI), m/z: 279 (M+H)⁺.

EXAMPLE 6 8-isopropoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.95 (d, J=8.0 Hz, 1H), 8.25˜8.28 (m,2H), 7.62˜7.63 (m, 3H), 7.27 (s, 1H), 7.11 (dd, J=8.0, 2.0 Hz, 1H), 6.87(s, 1), 5.02˜5.11 (m, J=6.0 Hz, 1H), 1.48 (d, J=6.0 Hz, 6H);

MS(ESI), m/z: 281 (M+H)⁺.

EXAMPLE 7 2-phenyl-8-propoxy-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.95 (d, J=8.0 Hz, 1H), 8.27˜8.28 (m,2H), 7.60˜7.64 (m, 3H), 7.19 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.88 (s,1H), 4.30 (t, J=6.4 Hz, 2H), 1.87˜1.95 (m, 2H), 1.12 (t, J=7.2 Hz, 3H);

MS(ESI), m/z: 281 (M+H)⁺.

EXAMPLE 8 3-ethyl-8-methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.84 (d, J=8.0 Hz, 1H), 7.56˜7.54 (m,5H), 7.00˜7.03 (m, 2H), 3.96 (s, 3H), 2.50 (q, J=7.2 Hz, 2H), 1.07 (t,J=7.2 Hz, 3H);

MS(ESI), m/z: 280 (M+H)⁺.

EXAMPLE 9 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₂), δ 9.02 (d, J=7.2 Hz, 1H), 8.04˜8.07 (m, 2H),7.68˜7.70 (m, 2H), 7.44˜7.48 (m, 3H), 7.06˜7.10 (m, 1H), 6.88 (s, 1H);

MS(ESI), m/z: 223 (M+H)⁺.

EXAMPLE 10 8-ethyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.97 (d, J=7.2 Hz, 1H), 8.07˜8.09 (m, 2H),7.60 (s, 1H), 7.49˜7.50 (m, 3H), 7.01 (d, J=7.6 Hz, 1H), 6.83 (s, 1H),2.79 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H);

MS(ESI), m/z: 251 (M+H)⁺.

EXAMPLE 11 8-methoxy-2-p-tolyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.92 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz,2H), 7.29 (d, J=8.0 Hz, 2H), 7.06 (s, 1H), 6.78 (dd, J=8.0, 2.4 Hz, 1H),6.70 (s, 1H), 3.98 (s, 3H), 2.41 (s, 3 H);

MS(ESI), m/z: 267 (M+H)⁺.

EXAMPLE 12 8-hydroxy-2-p-tolyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

MS(ESI), m/z: 253 (M+H)⁺.

EXAMPLE 13 8-ethoxy-2-p-tolyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.94 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz,2H), 7.31 (d, J=8.0 Hz, 2H), 7.26 (s, 1H), 6.80 (dd, J=8.0, 2.0 Hz, 1H),6.68 (s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.52 (t, J=7.2 Hz,3H);

MS(ESI), m/z: 281 (M+H)⁺.

EXAMPLE 14 2-(4-chlorophenyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.91 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.4 Hz,2H), 7.44 (d, J=8.4 Hz, 2H), 6.99 (s, 1H), 6.79 (dd, J=8.0, 2.0 Hz, 1H),6.66 (s, 1H), 3.98 (s, 3H);

MS(ESI), m/z: 287 (M+H)⁺.

EXAMPLE 15 2-(4-chlorophenyl)-8-hydroxy-4H-pyrido[1,2-a]pyrimidin-4one

Synthetic route is the same as shown in Example 1.

MS(ESI), m/z: 273 (M+H)⁺.

EXAMPLE 16 2-(3-chlorophenyl)-8-methoxy-4H-pyrido[1,2a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.66 (d, J=7.2 Hz, 1H), 8.06 (s, 1H), 7.85(dd, J=7.2, 1.2 Hz, 1H), 7.36-7.42 (m, 2H), 6.96 (s, 1H), 6.77 (d, J=8.0Hz, 1H), 6.65 (d, J=1.2 Hz, 1H), 3.96 (s, 3H);

MS(ESI), m/z: 287 (M+H)⁺.

EXAMPLE 17 2-(4-chlorophenyl)-8-ethoxy-4H-pyrido[1,2a]pyrimidin-4-one

Synthetic route is same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 9.05 (d, J=8.0 Hz, 1H), 8.12 (d, J=8.8 Hz,2H), 7.58 (d, J=8.4 Hz, 2H), 7.38 (s, 1H), 6.93 (dd, J=8.0, 2.0 Hz, 1H),6.77 (s, 1H), 4.36 (q, J=6.8 Hz, 2H), 1.64 (t, J=6.8 Hz, 3H);

MS(ESI), m/z: 301 (M+H)⁺.

EXAMPLE 18 2-(2-chlorophenyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.96 (d, J=8.0 Hz, 1H), 7.56˜7.59 (m, 1H),7.45˜7.48 (m, 1H), 7.34˜7.37 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.82 (dd,J=7.6, 2.4 Hz, 1H), 6.54 (s, 1H), 3.95 (s, 3H);

MS(ESI), m/z: 287 (M+H)⁺.

EXAMPLE 19 8-ethyl-3-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 8.85 (d, J=7.2 Hz, 1H), 7.59˜7.61 (m,2H), 7.47˜7.52 (m, 3H), 7.45 (s, 1H), 7.23 (dd, J=7.2, 1.6 Hz, 1H), 2.74(q, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.25 (t, J=7.2 Hz, 3H);

MS(ESI), m/z: 265 (M+H)⁺.

EXAMPLE 20

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl_(d6)), δ 9.02 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.0 Hz,2H), 7.54˜7.60 (m, 3H), 7.35 (d, J=0.8 Hz, 1H), 6.91 (dd, J=8.0, 1.6 Hz,1H), 4.29 (q, J=6.8 Hz, 2H), 2.32 (s, 3H), 1.59 (t, J=6.8 Hz, 3H);

MS(ESI), m/z: 281 (M+H)⁺.

EXAMPLE 21 8-hydroxy-3-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, DMSO-_(d6)), δ 9.00 (d, J=7.6 Hz, 1H), 7.60˜7.67 (m,5H), 7.21 (dd, J=7.6. 2.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 2.02 (s, 3H);

MS(ESI), m/z: 253 (M+H)⁺.

EXAMPLE 22 6-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.06 (t, 2H), 7.42˜7.56 (m, 5H), 6.72 (s, 1H),6.65 (d, J=6.8 Hz, 1H), 3.08 (s, 3H);

MS(ESI), m/z: 237 (M+H)⁺.

EXAMPLE 23 7-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.89 (s, 1H), 8.07˜8.09 (m, 2H), 7.77 (d,J=9.2 Hz, 1H), 7.65 (dd,J=9.2, 1.6 Hz, 1H), 7.49˜7.52 (m, 3H), 6.88 (s,1H), 2.45 (s, 3H);

MS(ESI), m/z: 237 (M+H)⁺.

EXAMPLE 24 8-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.96 (d, J=7.2 Hz, 1H), 8.07˜8.09 (m, 2H),7.65 (s, 1H), 7.48˜7.50 (m, 3H), 6.98 (d, J=7.2 Hz, 1H), 6.82 (s, 1H),2.50 (s, 3H);

MS(ESI), m/z: 237 (M+H)⁺.

EXAMPLE 25 9-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.97 (d, J=7.2 Hz, 1H), 8.16˜8.18 (m, 2H),7.61 (d, J=6.8 Hz, 1H), 7.50˜7.51 (m, 3H), 7.02˜7.06 (t, 1H), 6.95 (s,1H), 2.71 (s, 3H);

MS(ESI), m/z: 237 (M+H)⁺.

EXAMPLE 268-(3-morpholinopropoxy)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.79 (d, J=7.6 Hz, 1H), 8.13˜8.14 (m, 2H),7.45˜7.49 (m, 3H), 7.05 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.73 (s, 1H),4.23 (t, J=5.6 Hz, 2H), 3.51˜3.55 (m, 4H), 2.28˜2.41 (m, 6H), 1.90 (t,J=6.4 Hz, 2H);

MS(ESI), m/z: 366 (M+H)⁺.

EXAMPLE 27 8-chloro-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Synthetic route is the same as shown in Example 1.

¹HNMR (400 MHz, CDCl₃), δ 8.98 (d, J=7.2 Hz, 1H), 8.07˜8.08 (m, 2H),7.82 (s, 1H), 7.50˜7.52 (m, 3H), 7.09 (d, J=7.6 Hz, 1H), 6.88 (s, 1H);

MS(ESI), m/z: 257 (M+H)⁺.

EXAMPLE 28

Current example illustrates that the compounds mentioned in thisinvention (such as the compound in Example 10, also named DK45,8-ethyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one) and other compoundswith core structure of Formula VIII such as the compound of Example 1,also named DK36, 8-methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4one, andthe compound of Example 6, also named DK41,8-isopropoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, can effectivelyenhance the expression of reporter genes modulated by ERRα in 293FTcell, therefore these compounds can effectively enhance the function ofERRα.

To test the effect of the compounds on ERR and other nuclear hormonereceptors, 293FT cells were transiently transferred with expressionvectors for the receptors along with appropriate reporter constructsaccording to methods known in the art. Suitable reporter gene constructsare well known to skilled workers in the fields of biochemistry andmolecular biology. Other vectors known in the art can be used in themethods of the present invention.

GAL4 fusions containing receptor ligand binding domain fragments wereconstructed by fusing human ERRα, human ERRβ and murine ERRγ ligandbinding domain sequences to the C-terminal end of the yeast GAL4 DNAbinding domain (amino acids 1-147 accession X85976) to form theexpression vectors GAL-hERRα, GAL-L-hERRβ and Gai-mERRγ, respectively.pGAL is a control containing the yeast GAL4 DNA binding domain withoutreceptor sequences, CMV-PGC-1α contains and expressed the PGC-1α codingsequences derived from PGC-1α (accession NM.sub.008904).

293FT cells for the activation assays were grown in Dulbecco's modifiedEagle's medium supplemented with 10% resin charcoal-stripped fetalbovine serum at 37° C. in 5% CO₂. One day prior to transaction, cellswere plated to 50-80% confluence using phenol red free DMEM-FBS. Thecells were transiently transfected by lipofection but other methods oftransfection of DNA into cells can be utilized without deviating fromthe spirit of the invention. Luciferase reporter construct UASgx4-TK-Lucand cytomegalovirus-driven expression vector p-GAL, GAL-hERRα,GAL-L-hERRβ or Gai-mERRγ were added with CMV-PGC-1α. The cells weretreated for approximately 24 hours with phenol red free DMEM-FBScontaining 0.01% DMSO (control) or 0.01% DMSO with increasingconcentrations of DK compounds.

The compound of Example 10, also named DK45,8-ethyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one and other compoundswith core structure of Formula VIII as the compound of Example 1, alsonamed DK36, 8-methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, andcompound of Example 6, also named DK41,8-isopropoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, dose-dependentlyenhances the activity of GAL-hERRα on reporter construct UASgx4-TK-Locin the presence of CMV-PGC-1α. (FIG. 1). These suggested that thesecompounds functioned to increase the activity of ERRα.

EXAMPLE 29

Current example illustrates that compounds mentioned in this inventionsuch as DK45 can effectively enhance the expression of PGC1α-promoterreporter gene and PDK4-promoter reporter gene in HeLa cell.

HeLa ware transiently transacted with the pGL3-promoter (Promega)derivative pGL3-PGC1α-promoter or PDK4-Promega and expression vector forERRα. The Renilla-Luciferase pRL-CMV Vector (Promega) was included as acontrol for transfection efficiency. The full length human ERRα wascloned into the expression vector pCMV. The pGL3-PGC1α-promoter orPDK4-promoter was generated by cloning an insert derived from a PCRreaction using human genomic DNA as template and primers based on the2.6 kbp upstream sequence of the PGC1α transcriptional start site.

HeLa cells for the activation assays were grown in Dulbecco's modifiedEagle's medium supplemented with 10% fetal bovine serum at 37° C. in 5%CO₂. One day prior to transfection, cells were plated to 50-80%confluence using DMEM-FBS. The cells were transiently transfected bylipofection but other methods of transfection of DNA into cells can beutilized without deviating from the spirit of the invention. Luciferasereporter construct pGL3-PGC1α-promoter or PDK4-promoter andcytomegalovirus-driven expression vector pCMV or pCMV-hERRα were added.The cells were treated for approximately 24 hours with DMEM-FBScontaining 0.01% DMSO (control) or 0.01% DMSO with 10 μM DK45 compound.

The enhancement of the PGC1α-promoter reporter gene and PDK4-promoterreporter gene driven by ERRα was observed for the compound DK45 (FIG.2).

EXAMPLE 30

Current example illustrates that compounds mentioned in this inventionsuch as DK45, can effectively improve glucose tolerance in high-fat-dietmice.

Seven weeks old male C57BL/J6 mice were either fed chow diet or ahigh-fat-diet with 60% calories from lard for 10 weeks. Compounds wereadministered to animals by gavage for two weeks at different doses. Fourgroups of animals (n=5) were administered with either vehicle, 5mg/kg/day rosiglitazone, or 5 mg/kg/day DK45. Animals were fasted for 5h, and then orally fed glucose. Blood samples were withdrawn at time 0,15, 30, 60 and 120 min. Blood glucose level was measured by monitor(Accu-chek Advantage, Roche). The changes in blood glucose level wereplotted against time and the areas under the curve were calculated torthe different groups.

Compared to positive control rosiglitazone given at 5 mg/kg/day, DK45 at5 mg/kg/day reduced the area under the curve of the oral glucosetolerances test, indicating that ERRα agonists DK45 improve glucosetolerance in vivo (FIG 3). Non-fasting treatments also suggest that DK45at 5 mg/kg/day reduced the blood glucose levels.

In addition, insulin resistance test was administered. Animals werefasted for 5 h, and then injected insulin (0.75 IU/kg). Blood sampleswere withdrawn at time 0, 15, 30, 60 and 120 min. Blood glucose levelwas measured by monitor (Accu-chek Advantage, Roche). The changes inblood glucose level were plotted against time and the areas under thecurve were calculated for the different groups.

Compared to positive control rosiglitazone given at 5 mg/kg/day, DK45 at5 mg/kg/day reduced the area under the curve of the insulin resistancetest, indicating that ERRα agonists DK45 improve insulin sensitivity invivo (FIG. 5). The blood insulin levels of fasting and non-fastingtreatments also indicate that DK45 at 5 mg/kg/day reduced the bloodinsulin levels of non-fasting treatments (FIG. 6).

Moreover, DK45 at 5 mg/kg/day reduced serum free fatty acid (FIG. 7),cholesterol (FIG. 8), and triglyceride levels (FIG. 9) of non-fastingtreatments.

What is claimed is:
 1. A compound of Formula VIII or a pharmaceuticallyacceptable salt or stereoisomer thereof:

wherein: m is 0, 1 or 2; n is 1 or 2; in the following, a is 0 or 1, bis 0 or 1; each occurrence of R₁ is independently selected from thegroup consisting of: 1) Halo; 2) OH; 3) (C═O)_(a)O_(b)C₁-C₄ alkyl; and4) (C═O)_(a)O_(b)C₃-C₆ cycloalkyl, wherein one occurrence of R₁ is atthe 8-position of the pyrido[1,2-a]pyrimidin-4-one ring; each occurrenceof R₂ is independently selected from the group consisting of: 1) Halo;2) OH; 3) (C═O)_(a)O_(b)C₁-C₄ alkyl, wherein, if a is 0 and b is 1, thealkyl is substituted with C₃-C₆ heterocyclyl; or 4) (C═O)_(a)O_(b)C₃-C₆cycloalkyl; wherein, if one occurrence R₇ is halo or C₁-C₄ alkyl, atleast one occurrence of R₁ is OH or (C═O)_(a)O_(b)C₁-C₄ alkyl wherein ais 0 and b is 1; R₂ is selected from the group consisting of: 1) H; 2)C₁-C₃ alkyl; and 3) C₃-C₆ cycloalkyl; the alkyl mentioned above can besubstituted by 0, 1 or more substituted R₄ groups wherein R₄ is selectedfrom the group consisting of: 1) H; and 2) C₃-C₆ heterocyclyl,
 2. Acompound or pharmaceutically acceptable salt or stereoisomer thereofwherein the compound is selected from the group consisting of:


3. A pharmaceutical composition comprising a compound or apharmaceutically acceptable salt or stereo isomer according to claim 1and a pharmaceutically acceptable carrier.
 4. A method of treating ametabolic disease, the method comprising administering an effectiveamount of a composition of claim 3 to a patient in need thereof.
 5. Themethod of claim 4, wherein the metabolic disease is: (1) Type IIdiabetes; (2) hyperglycemia; (3) reduced glucose tolerance; (4) insulinresistance; (5) obesity; (6) abnormal fat metabolism; (7) dyslipidemia;(8) hyperlipidemia; (9) hypertriglyceridemia; (10) hypercholesterolemia;(11) low levels of HDL; (12) high levels of LDL; (13) atherosclerosis;(14) vascular restenosis; (15) central obesity; (16) metabolic syndrome;or (17) fatty liver.
 6. A pharmaceutical composition comprising acompound or a pharmaceutically acceptable salt or stereoisomer accordingto claim 2 and a pharmaceutically acceptable carrier.